1. Field of the Invention
The present invention relates to a treatment of ocular hypertension with a synergistic combination comprising (a) a 13,14-dihydro-15-ketoprostaglandin compound and (b) a .beta.-adrenergic blocker.
The compounds used as the component (a) in the present invention are prostaglandin analogues which can be obtained synthetically.
2. Information of Prior Art
Prostaglandins (hereinafter, prostaglandins are referred to as PGs) are members of a class of organic carboxylic acid that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities. Naturally occurring PGs possess as a common structural feature the prostanoic acid skeleton: ##STR1## Some synthetic analogues have somewhat modified skeletons. The primary PGs are classified based on the structural feature of the five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
Subscript 1: 13,14-unsaturated-15-OH PA1 Subscript 2: 5,6- and 13,14-diunsaturated-15-OH PA1 Subscript 3: 5,6- 13,14- and 17,18-triunsaturated-15-OH PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a .beta.-adrenergic blocker PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a .beta.-adrenergic blocker PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a .beta.-adrenergic blocker
Further, PGFs are sub-classified according to the configuration of hydroxy group at position 9 into .alpha.(hydroxy group being in the alpha configuration) and .beta.(hydroxy group being in the beta configuration).
The fact that the above compounds under item (a) have ocular hypotensive activity has been known by Japanese Patent Publication No. A-108/1990. It has also been described in Japanese Patent Publication No. A-313728/1988, page 7, column 3, line 7 from bottom to page 8, column 4, line 4, that a combination of PGF.sub.2 .alpha. isopropyl ester and Timolol (an agent for treating glaucoma) may be advantageous because the ocular hypotensive activity of the former is not inhibited by a .beta.-adrenergic blocker such as the latter. Such description, however, neither show a combined use of the .beta.-adrenergic blocker and the component (a) in the present invention nor suggest that said combined use may synergistic increase in effect or decrease in side-effect because PGF.sub.2 .alpha. is a primary PG having a trans double bond between positions 13 and 14, a hydroxy group (in .alpha.-conformation) at position 15 and 20 carbon atoms in the basic structure, while the 13,14-dihydro-15-keto-PGs are compounds having a saturated bond between positions 13 and 14, an oxo group at position 15 in place of a hydroxy group which has been considered as an important group for activities of primary PGs and thus significantly different from the primary PGF.sub.2 .alpha..
After an extensive study on the possibility that the effect of the component (a) in the present invention is improved by combining it with a variety of compounds, the present inventor has surprisingly discovered that the effect of the component (a) is significantly improved and side-effect is decreased by co-administration with a .beta.-adrenergic blocker such as Timolol. Said discovery leads to the present invention.